Age related macular degeneration remains the leading cause of visual loss in the United Kingdom and other developed countries. Oxidative damage in the retina has been hypothesised as a key process involved in development of early AMD. Antioxidants are thought to prevent AMD by reducing the photo-oxidative damage from blue light in the oxygen filled environment of the retina, which is rich in polyunsaturated fatty acids that are highly susceptible to oxidation.40
Previous studies and reviews have largely focused on the role of dietary antioxidants and supplements in the secondary prevention of AMD—that is, preventing progression to late AMD in people with signs of early disease. Our analysis examined the role of dietary antioxidants and supplements in primary prevention and found that a range of dietary antioxidants, including vitamins A, C, and E, zinc, lutein and zeaxanthin, α carotene, β carotene, β cryptoxanthin, and lycopene, have little or no effect: pooled odds ratios ranged from 0.91 to 1.11, with the exception of vitamin E, which had a modest borderline protective association (0.83, 95% confidence interval 0.69 to 1.01).
Comparison with other studies
We found few randomised clinical trials, none of which found that vitamin E and β carotene supplements prevented early AMD.w10-w12 The studies we evaluated were largely derived from populations in the United States or other developed Western nations, where participants are well nourished. Although we included both population based and volunteer based studies, the pooled odds ratio for the nutrients investigated, with the exception of vitamin E, did not change greatly in our sensitivity analyses of population based and high quality studies.
For vitamin E, the borderline significant pooled odds ratio, especially from the two high quality studies, suggests that vitamin E may be associated with a reduced risk of early AMD. Results from the two randomised control trials do not support a protective effect of vitamin E supplementation, given in doses 2.5-fold to 15-fold higher than the highest dietary range estimated from these cohort studies. The vitamin E, cataract, and age related maculopathy trial reported a relative risk for early AMD of 1.05 (0.69 to 1.61) comparing vitamin E intake of 335 mg/day versus placebo,w10 and the alpha tocopherol and beta carotene trial reported an odds ratio for any AMD of 1.27 (0.84 to 1.93) for vitamin E intake of 50 mg/day versus placebo.w11
The alpha tocopherol and beta carotene trial reported an odds ratio for any AMD of 1.17 (0.76 to 1.79) for β carotene intake of 20 mg/day versus placebo,w11 and the physicians' health study reported a relative risk of 0.97 (0.81 to 1.15) for β carotene (50 mg every other day) versus placebo.w12 These results are consistent with data from prospective cohort studies. The pooled odds ratio of dietary β carotene intake for early AMD was 1.04 (0.85 to 1.27), comparing the highest (range of intake of 6.2-11.9 mg/day) to the lowest (2.1-2.3 mg/day) category of dietary β carotene.
Carotenoids have been shown to be good filters of harmful blue light, and their antioxidative properties have been demonstrated in vitro.41
Two of these carotenoids, lutein and zeaxanthin, are found in the macula in concentrations higher than in other parts of the body.42
However, results from our review suggest that high antioxidant levels in the healthy retina do little to prevent the development of early AMD. A Cochrane review showed that antioxidant supplements may have a role delaying the progression of early to late AMD.43
These contrasting results could imply that uncontrolled oxidative chain reactions of reactive oxygen species may have begun in eyes with AMD at early or intermediate stage, and thus high antioxidant levels at this stage of the disease process may be effective in slowing progression of AMD. The Cochrane review reported a protective effect from multivitamin supplementation (pooled odds ratio 0.68, 99% confidence interval 0.49 to 0.93) and a protective effect of zinc supplementation (0.73, 95% confidence interval 0.58 to 0.93) in preventing the progression of AMD. Both findings were mainly based on data from the age related eye disease study.22
No protective effect was seen for vitamin E supplementation (1.05, 0.80 to 1.55; derived only from the vitamin E, cataract, and age related maculopathy trialw10
Strengths and weaknesses of the study
We sought to be as comprehensive as possible, in accordance with guidelines for meta-analyses,34 44
and performed an extensive search through seven databases, including grey literature, and did not limit our searches by language or time.45 46
Inclusion of grey literature has also been shown to reduce the likelihood of publication bias47
and of overestimating pooled estimates.32
Although only six studies evaluated lutein and zeaxanthin, the funnel plot showed an inverted V shape, suggesting that publication bias was unlikely.38 39
Furthermore, we had prespecified the inclusion criteria for the studies, and we specifically evaluated dietary antioxidant intakes and AMD outcomes. Studies that were included had adequate follow-up (most studies lasted a decade), had sound methods, and were of good quality. All studies with pooled risk estimates had been adjusted for age, cigarette smoking, and energy intake in the analyses and had results that were consistent with one another. Overall, there was also little heterogeneity between studies that were included in this review.
Limitations in published studies
Our review identified important limitations in the current literature. Firstly, we found few randomised controlled trials. Our meta-analysis did not include the results of the age related eye disease study, which evaluated the role of antioxidant supplements in the secondary prevention of AMD, a topic that is outside the scope of our review. Of the primary prevention trials, the two published randomised controlled trials evaluated only two potential antioxidants (vitamin E and β carotene) and had a relatively short follow-up of 4-6 years. Thus, prospective cohort studies provided the best currently available evidence regarding dietary antioxidants in the primary prevention of AMD. These prospective studies showed little heterogeneity, allowing us to conduct meta-analysis to derive pooled estimates of risk, but meta-analysis of observational data is known to have more biases than meta-analysis of randomised controlled trials.48
Secondly, we are unable to evaluate the effect of potential antioxidant synergism in our review. In the Rotterdam eye study, an above median dietary intake of combined antioxidant nutrients, similar to those found in the clinical trial formulation of the age related eye disease study, was associated with a larger reduced risk of AMD than for each antioxidant (vitamin C, vitamin E, β carotene, zinc) individually.w1 We were unable to evaluate such potential synergistic effects with particular antioxidant intake combinations or ratios, as individual studies evaluated each antioxidant in isolation and we pooled the results for each antioxidant separately.
Thirdly, although the included studies had participation rates of greater than 80%, participants in some of these (healthcare professionals, for example) may not be representative of the wider community. Moreover, all studies were conducted in relatively well nourished populations in the United States and other developed Western countries, and results may not be generalisable to other countries.
Fourthly, the assessment and definition of AMD varied between studies (see table 1). Definitions ranged from those based on photographs to those that included visual acuity criteria. Studies that included visual acuity criteria may have included a smaller proportion of cases of early AMD than those studies with photographic documentation only.
Finally, most studies used food frequency questionnaires to assess dietary intakes of antioxidants, and these questionnaires were administered only once at study baseline. Non-differential misclassification of antioxidant intake may have occurred, which may bias the results towards the null.
Dietary intake of nine antioxidants evaluated in this systematic review had little or no effect in the primary prevention of early AMD in well nourished Western populations. There is insufficient evidence that antioxidants supplements prevent the onset of AMD. Cigarette smoking remains the only widely accepted modifiable risk factor for the primary prevention of AMD, and patients seeking advice on AMD prevention should be encouraged to stop smoking.
What is already known about this topic
- Age related macular degeneration (AMD) is the leading cause of visual loss in older people
- Antioxidants have been hypothesised to reduce oxidative damage to the retina, but the effectiveness of dietary antioxidants in the primary prevention of AMD is unclear
What this study adds
- Dietary antioxidants had little or no effect in the primary prevention of early AMD in well nourished Western populations
- Cigarette smoking remains the only widely accepted modifiable risk factor for the primary prevention of AMD